Compositions and methods for the treatment of eye disorders

ABSTRACT

Aspects of the present disclosure provide compound of Formula I and pharmaceutically acceptable hydrates, solvates, crystals, co-crystals, enantiomers, stereoisomers, polymorphs and prodrugs thereof that can find utility in treatment of eye disorders and complications associated therewith. Aspects of the present disclosure also relate to methods of treating an eye disorder and/or complications thereof in a subject in need thereof by administering the compound of Formula I or a pharmaceutically acceptable hydrate, solvate, crystal, enantiomer, stereoisomer, polymorph or prodrug thereof. 
                         
wherein, X +  represents,

PRIORITY

The present application is a continuation of International PatentApplication No. PCT/IB2018/057342, which was filed Sep. 22, 2018, whichclaims the benefit of Indian Provisional Application No. IN201741041231filed on Nov. 17, 2017, the contents of which are incorporated in theirentirety herein by reference.

TECHNICAL FIELD

The present disclosure generally relates to compounds and compositionsfor the treatment of eye disorders. More particularly, the presentdisclosure relates to new compounds and crystals, solvates, enantiomers,stereoisomers, esters, polymorphs, co-crystals and hydrates thereof thatcan find utility in management of eye disorders. Aspects of the presentdisclosure also relates to treatment of subjects with a pharmaceuticallyacceptable dose of compound(s), crystals, solvates, enantiomer,stereoisomer, esters, hydrates, or mixtures thereof.

BACKGROUND

Background description includes information that may be useful inunderstanding the present invention. It is not an admission that any ofthe information provided herein is prior art or relevant to thepresently claimed invention, or that any publication specifically orimplicitly referenced is prior art.

Age-related eye diseases, in many cases are not sudden but tend todevelop slowly as a person ages. Of many age-related eye diseases, thereare four major diseases that are recognized, which can be detected andtreated if a comprehensive eye examination is performed. These fourage-related eye diseases—Macular Degeneration, Cataract, Glaucoma andDiabetic Retinopathy are expected to dramatically increase if leftuntreated and can cause vision loss and blindness. Population that ismost at risk for developing eye disease is unaware of the factors thatmake them susceptible. As the proportion of the elderly populationincreases around the world, the prevalence and effects of age-relatedeye diseases are also increasing. The leading causes of blindness andlow vision are primarily age-related eye diseases such as age-relatedmacular degeneration, cataract, diabetic retinopathy, and glaucoma.Age-related cataract will become an even larger percentage of the causesof blindness worldwide, and glaucoma and age-related maculardegeneration will emerge as public health issues.

Most common eye problems include Refractive errors, Cataracts—cloudedlenses, Optic nerve disorders, including glaucoma, Retinaldisorders—problems with the nerve layer at the back of the eye, Maculardegeneration—a disease that destroys sharp, central vision, Diabetic eyeproblems and Conjunctivitis—an infection also known as pinkeye.Presbyopia is progressive loss of accommodation resulting in loss ofvisual ability to focus on objects located at different distances.Accommodation in humans is performed by ciliary muscle and irissphincter contractions, convergence and changes in the shape andposition of the lens. The latter action is passive, meaning the lenschanges are dependent on the ciliary muscle and iris contractions. Also,when the centre of the accommodation is active, the ciliary musclecontraction is stimulated and miosis and convergence occurs in normalbinocular patients.

Published WO document WO2018065831 (Intl. Appl. No. PCT/IB2017/052237)discloses pilocarpine-(R)-lipoate for treatment of Xerostomia, SjogrensSyndrome and Dry Mouth, contents of which are incorporated in itsentirety herein by reference. However, it fails to suggest utilitythereof in treatment of eye disorders and complications associatedtherewith.

Managing acute pathology often relies on the addressing the underlyingpathology and symptoms of the disease. There is currently a need in theart for new compounds and compositions that can find utility in thetreatment of eye disorders and/or in delaying the onset of eye disordersand complications associated therewith.

OBJECTS OF THE INVENTION

An object of the present disclosure is to provide compounds andcrystals, co-crystals, solvates, enantiomer, stereoisomer, esters,hydrates, or mixtures thereof that can find utility in treatment of eyedisorders.

Another object of the present disclosure is to provide a pharmaceuticalcomposition for treatment of eye disorders.

SUMMARY

The present disclosure generally relates to compounds and compositionsfor the treatment of eye disorders. More particularly, the presentdisclosure relates to compounds and pharmaceutically acceptable salts,hydrates, solvates, crystals, co-crystals, enantiomers, stereoisomers,esters, polymorphs or prodrugs thereof that can find utility intreatment of eye disorders. Aspects of the present disclosure alsorelates to treatment of subjects with a pharmaceutically acceptable doseof the compound or pharmaceutically acceptable salts, crystals,solvates, enantiomer, stereoisomer, esters or hydrates thereof.

An aspect of the present disclosure provides a compound of formula I,

or a pharmaceutically acceptable hydrate, solvate, crystal, co-crystal,enantiomer, stereoisomer, polymorph or prodrug thereof,

wherein, X⁺ represents,

wherein said compound finds use in treatment of eye disorder orcomplications associated therewith. The eye disorder that can be treatedby the compound of formula I of the present disclosure includes maculardegeneration, cataract, glaucoma, diabetic retinopathy, dry eye, ocularneuritis, retinitis pigmentosa and presbyopia.

In an embodiment, the compound of formula I can bepilocarpine-RS-lipoate which is selected from:

In another embodiment, the compound of Formula I can bepilocarpine-(R)-lipoate which is selected from:

In another embodiment, the compound of Formula I can bepilocarpine-(S)-lipoate which is selected from:

In an embodiment, the compound of Formula I comprisespilocarpine-(R)-lipoate with an enantiomeric excess (ee) of at least 1%.In an embodiment, the compound of Formula I comprisespilocarpine-(S)-lipoate with an enantiomeric excess (ee) of at least 1%.

In an embodiment, the compound of formula I is any of

Another aspect of the present disclosure is directed to a pharmaceuticalcomposition for treating an eye disorder or complications thereof, whichcomprises a compound of formula I or a pharmaceutically acceptablehydrate, solvate, crystal, co-crystal, enantiomer, stereoisomer,polymorph or prodrug thereof and a pharmaceutically acceptableexcipient. In an embodiment, the pharmaceutical composition isformulated for oral, nasal, topical, rectal, vaginal, aerosol orparenteral administration. In certain preferred embodiments, thepharmaceutical composition is a topical ophthalmic formulation. Incertain preferred embodiments, the pharmaceutical composition is anophthalmic drop formulation.

Another aspect of the present disclosure provides a method of synthesisof pilocarpine-lipoate, the method comprising: treating pilocarpine withlipoic acid at a suitable temperature to obtain pilocarpine-lipoate. Inan embodiment, the method further comprises a step of contactingpilocarpine HCl with a base to obtain pilocarpine. In an embodiment, themethod comprises treating pilocarpine HCl in a solvent with a base toobtain pilocarpine. In an embodiment, the method comprises treatingpilocarpine HCl in acetone with sodium hydrogen carbonate for about 18 hat room temperature to obtain pilocarpine. In an embodiment, the methodeffects yield of about 100%. In an embodiment, the method furthercomprises a step of effecting recrystallization of thepilocarpine-lipoate. In an embodiment, the step of effectingrecrystallization comprises effecting recrystallization ofpilocarpine-lipoate with ethyl acetate (5 volumes) at 50-55° C. toobtain crystalline pilocarpine-lipoate with yield of about 80%.

Another aspect of the present disclosure provides a method of treatingan eye disorder or complications thereof in a subject in need thereof,the method comprising administering to the subject a therapeuticallyeffective amount of the compound of formula I disclosed herein or apharmaceutically acceptable hydrate, solvate, crystal, co-crystal,enantiomer, stereoisomer, polymorph or prodrug thereof. In anembodiment, the eye disorder that can be treated by the method disclosedherein can include macular degeneration, cataract, glaucoma, diabeticretinopathy, dry eye, ocular neuritis, retinitis pigmentosa andpresbyopia.

In yet another aspect, the present disclosure is directed to use of thecompound of formula I or a pharmaceutically acceptable hydrate, solvate,crystal, co-crystal, enantiomer, stereoisomer, polymorph or prodrugthereof for manufacture of a medicament for treatment of an eye disorderor complications associated therewith.

Various objects, features, aspects and advantages of the inventivesubject matter will become more apparent from the following detaileddescription of preferred embodiments, along with the accompanyingdrawing figures in which like numerals represent like components.

DETAILED DESCRIPTION

The following is a detailed description of embodiments of the disclosuredepicted in the accompanying drawings. The embodiments are in suchdetail as to clearly communicate the disclosure. However, the amount ofdetail offered is not intended to limit the anticipated variations ofembodiments; on the contrary, the intention is to cover allmodifications, equivalents, and alternatives falling within the spiritand scope of the present disclosure as defined by the appended claims.

Each of the appended claims defines a separate invention, which forinfringement purposes is recognized as including equivalents to thevarious elements or limitations specified in the claims. Depending onthe context, all references below to the “invention” may in some casesrefer to certain specific embodiments only. In other cases it will berecognized that references to the “invention” will refer to subjectmatter recited in one or more, but not necessarily all, of the claims.

As used in the description herein and throughout the claims that follow,the meaning of “a,” “an,” and “the” includes plural reference unless thecontext clearly dictates otherwise. Also, as used in the descriptionherein, the meaning of “in” includes “in” and “on” unless the contextclearly dictates otherwise.

All methods described herein can be performed in any suitable orderunless otherwise indicated herein or otherwise clearly contradicted bycontext. The use of any and all examples, or exemplary language (e.g.“such as”) provided with respect to certain embodiments herein isintended merely to better illuminate the invention and does not pose alimitation on the scope of the invention otherwise claimed. No languagein the specification should be construed as indicating any non-claimedelement essential to the practice of the invention.

Various terms as used herein are shown below. To the extent a term usedin a claim is not defined below, it should be given the broadestdefinition persons in the pertinent art have given that term asreflected in printed publications and issued patents at the time offiling.

The term “isomers” as used herein throughout the present disclosureencompasses within its meaning, the compounds that have same molecularformula but differ in the nature or sequence of bonding of their atomsor arrangement of their atoms in space.

The term “stereoisomer” as used herein throughout the present disclosureencompasses within its meaning, isomers that differ in the arrangementof their atoms in space.

The term “diastereomer” as used herein throughout the present disclosureencompasses within its meaning, stereoisomers with oppositeconfiguration at one or more chiral centers, which are not enantiomers.

The term “enantiomer” as used herein throughout the present disclosureencompasses within its meaning, stereoisomers bearing one or moreasymmetric centers that are non-superimposable mirror images of eachother. When a compound has one asymmetric center, for example, if acarbon atom is bonded to four different groups, a pair of enantiomers ispossible. An enantiomer can be characterized by the absoluteconfiguration of its asymmetric center or centers and is described bythe R- and S-sequencing rules of Cahn, Ingold and Prelog (CIP), or bythe manner in which the molecule rotates the plane of polarized lightand designated as dextrorotatory or levorotatory (i.e., as (+) or(−)-isomers respectively). A chiral compound can exist as eitherindividual enantiomer or as a mixture thereof. A mixture containingequal proportions of the enantiomers is called a “racemic mixture”.

The term “polymorph” as used herein is art-recognized and refers to acrystal structure of a given compound.

The phrases “parenteral administration” and “administered parenterally”as used herein refer to modes of administration other than enteral andtopical administration, such as injections, and include intravenous,intramuscular, intrapleural, intravascular, intrapericardial,intraarterial, intrathecal, intracapsular, intraorbital, intracardiac,intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular,intra-articular, subcapsular, subarachnoid, intraspinal and intrastemalinjection and infusion, but not limited thereto.

A “patient,” “subject,” or “host” to be treated by the subject methodmay mean either a human or non-human animal, such as primates, mammals,and vertebrates.

The phrase “pharmaceutically acceptable” is art-recognized. In certainembodiments, the term includes compositions, polymers and othermaterials and/or dosage forms which are, within the scope of soundmedical judgment, suitable for use in contact with the tissues ofmammals, human beings and animals without excessive toxicity,irritation, allergic response, or other problem or complication,commensurate with a reasonable benefit/risk ratio.

The phrase “pharmaceutically acceptable excipient” is art-recognized,and includes, for example, pharmaceutically acceptable materials,compositions or vehicles, such as a liquid or solid filler, diluent,solvent or encapsulating material involved in carrying or transportingany subject composition, from one organ, or portion of the body, toanother organ, or portion of the body. Each carrier must be “acceptable”in the sense of being compatible with the other ingredients of a subjectcomposition and not injurious to the patient. In certain embodiments, apharmaceutically acceptable carrier is non-pyrogenic. Some examples ofmaterials which may serve as pharmaceutically acceptable carriersinclude: (1) sugars, such as lactose, glucose and sucrose; (2) starches,such as corn starch and potato starch; (3) cellulose, and itsderivatives, such as sodium carboxymethyl cellulose, ethyl cellulose andcellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7)talc; (8) cocoa butter and suppository waxes; (9) oils, such as peanutoil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil andsoybean oil; (10) glycols, such as propylene glycol; (11) polyols, suchas glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters,such as ethyl oleate and ethyl laurate; (13) agar; (14) bufferingagents, such as magnesium hydroxide and aluminum hydroxide; (15) alginicacid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer'ssolution; (19) ethyl alcohol; (20) phosphate buffer solutions; and (21)other non-toxic compatible substances employed in pharmaceuticalformulations.

The term “prodrug” is intended to encompass compounds that, underphysiological conditions, are converted into the therapeutically activeagents of the present disclosure. A common method for making a prodrugis to include selected moieties that are hydrolyzed under physiologicalconditions to reveal the desired molecule. In other embodiments, theprodrug is converted by an enzymatic activity of the host animal.

The term “prophylactic or therapeutic” treatment is art-recognized andincludes administration to the host of one or more of the compositions.If it is administered prior to clinical manifestation of the unwantedcondition (e.g., disease or other unwanted state of the host animal)then the treatment is prophylactic, i.e., it protects the host againstdeveloping the unwanted condition, whereas if it is administered aftermanifestation of the unwanted condition, the treatment is therapeutic,(i.e. it is intended to diminish, ameliorate, or stabilize the existingunwanted condition or side effects thereof).

The term “treating” or “treatment” is art recognized and includespreventing a disease, disorder or condition from occurring in a humanbeing or an animal, which may be predisposed to the disease, disorderand/or condition but has not yet been diagnosed as having it; inhibitingthe disease, disorder or condition, e.g., impeding its progress; andrelieving the disease, disorder, or condition, e.g., causing regressionof the disease, disorder and/or condition. Treating the disease orcondition includes ameliorating at least one symptom of the particulardisease or condition, even if the underlying pathophysiology is notaffected, such as treating Disorders of eyelid, lacrimal system andorbit, Disorders of conjunctiva, Disorders of sclera, cornea, iris andciliary body, Disorders of lens, Disorders of choroid and retina,Glaucoma, Disorders of vitreous body and globe, Disorders of optic nerveand visual pathways, Visual disturbances and blindness, Presbyopia andother related diseases or any other medical condition, is wellunderstood in the art, and includes administration of a compositionwhich reduces the frequency of, or delays the onset of, symptoms of amedical condition in a subject relative to a subject which does notreceive such composition.

The phrase “therapeutically effective amount” is an art-recognized term.In certain embodiments, the term refers to an amount of a solvate orhydrate or composition disclosed herein that produces some desiredeffect at a reasonable benefit/risk ratio applicable to any medicaltreatment. In certain embodiments, the term refers to that amountnecessary or sufficient to eliminate or reduce medical symptoms for aperiod of time. The effective amount may vary depending on such factorsas the disease or condition being treated, the particular targetedconstructs being administered, the size of the subject, or the severityof the disease or condition. One of ordinary skill in the art mayempirically determine the effective amount of a particular compositionwithout necessitating undue experimentation.

As used herein, the term “ophthalmic composition” refers to acomposition intended for application to the eye or its related orsurrounding tissues such as, for example, the eyelid or onto the cornea.The term also includes compositions intended to therapeutically treatconditions of the eye itself or the tissues surrounding the eye. Theophthalmic composition can be applied topically or by other techniques,as known to or appreciated by persons skilled in the pertinent art, suchas injection to the eye. Examples of suitable topical administration tothe eye include administration in form of eye drops and by sprayformulations. A further suitable topical administration route is bysubconjunctival injection. The compositions can also be provided to theeye periocularly or retro-orbitally.

In certain embodiments, the pharmaceutical compositions described hereinare formulated in a manner such that said compositions will be deliveredto a patient in a therapeutically effective amount, as part of aprophylactic or therapeutic treatment. The desired amount of thecomposition to be administered to a patient will depend on absorption,inactivation, and excretion rates of the drug as well as the deliveryrate of the hydrates or solvates and compositions from the subjectcompositions. It is to be noted that dosage values may also vary withthe severity of the condition to be alleviated. It is to be furtherunderstood that for any particular subject, specific dosage regimensshould be adjusted over time according to the individual need and theprofessional judgment of the person administering or supervising theadministration of the compositions. Typically, dosing will be determinedusing techniques known to one skilled in the art.

Additionally, the optimal concentration and/or quantities or amounts ofany particular solvate or hydrate or composition may be adjusted toaccommodate variations in the treatment parameters. Such treatmentparameters include the clinical use to which the preparation is put,e.g., the site treated, the type of patient, e.g., human or non-human,adult or child, and the nature of the disease or condition.

In certain embodiments, the dosage of the compounds of Formula Iprovided herein may be determined by reference to the plasmaconcentrations of the therapeutic composition or other encapsulatedmaterials. For example, the maximum plasma concentration (Cmax) and thearea under the plasma concentration-time curve from time 0 to infinitymay be used.

When used with respect to a pharmaceutical composition or othermaterial, the term “sustained release” is art-recognized. For example, asubject composition which releases a substance over time may exhibitsustained release characteristics, in contrast to a bolus typeadministration in which the entire amount of the substance is madebiologically available at one time. For example, in particularembodiments, upon contact with body fluids including blood, spinalfluid, mucus secretions, lymph or the like, one or more of thepharmaceutically acceptable excipients may undergo gradual or delayeddegradation (for example, through hydrolysis) with concomitant releaseof any material incorporated therein, e.g., an therapeutic and/orbiologically active solvate or hydrate and/or composition, for asustained or extended period (as compared to the release from a bolus).This release may result in prolonged delivery of therapeuticallyeffective amounts of any of the therapeutic agents (compounds) disclosedherein.

The phrases “systemic administration,” “administered systemically,”“peripheral administration” and “administered peripherally” areart-recognized, and include the administration of a subject composition,therapeutic or other material at a site remote from the disease beingtreated. Administration of an agent for the disease being treated, evenif the agent is subsequently distributed systemically, may be termed“local” or “topical” or “regional” administration, other than directlyinto the central nervous system, e.g., by subcutaneous administration,such that it enters the patient's system and, thus, is subject tometabolism and other like processes.

The present disclosure also contemplates prodrugs of the compositionsdisclosed herein, as well as pharmaceutically acceptable hydrates orsolvates of said prodrugs.

The present disclosure generally relates to compounds and compositionsfor the treatment of eye disorders. More particularly, the presentdisclosure relates to compounds and pharmaceutically acceptablecrystals, co-crystals, solvates, enantiomers, stereoisomers, prodrugs orhydrates thereof that can find utility in treatment of eye disorders.Aspects of the present disclosure also relate to methods of treating aneye disorder and/or complications thereof in a subject in need thereof.

An aspect of the present disclosure provides a compound of formula I,

or a pharmaceutically acceptable hydrate, solvate, crystal, co-crystal,enantiomer, stereoisomer, polymorph or prodrug thereof,

wherein, X⁺ represents,

wherein said compound finds use in treatment of eye disorder orcomplications associated therewith. The eye disorder that can be treatedby the compound of formula I of the present disclosure includes maculardegeneration, cataract, glaucoma, diabetic retinopathy, dry eye, ocularneuritis, retinitis pigmentosa and presbyopia.

In an embodiment, the compound of formula I can bepilocarpine-RS-lipoate which is selected from:

In an embodiment, the compound of Formula I can bepilocarpine-(R)-lipoate which is selected from:

In an embodiment, the compound of Formula I can bepilocarpine-(S)-lipoate which is selected from:

In an embodiment, the compound of Formula I comprisespilocarpine-(R)-lipoate with an enantiomeric excess (ee) of at least 1%.In an embodiment, the compound of Formula I comprisespilocarpine-(S)-lipoate with an enantiomeric excess (ee) of at least 1%.

In an embodiment, the compound of formula I is any of

Another aspect of the present disclosure is directed to a pharmaceuticalcomposition for treating an eye disorder or complications thereof, whichcomprises the disclosed compound of formula I or a pharmaceuticallyacceptable hydrate, solvate, crystal, co-crystal, enantiomer,stereoisomer, polymorph or prodrug thereof and a pharmaceuticallyacceptable excipient. In an embodiment, the pharmaceutical compositionis formulated for oral, nasal, topical, rectal, vaginal, aerosol orparenteral administration. In certain preferred embodiments, thepharmaceutical composition is a topical ophthalmic formulation. Incertain preferred embodiments, the pharmaceutical composition is anophthalmic drop formulation.

Another aspect of the present disclosure provides a method of synthesisof pilocarpine-lipoate, the method comprising: treating pilocarpine withlipoic acid at a suitable temperature to obtain pilocarpine-lipoate. Inan embodiment, the method further comprises a step of contactingpilocarpine HCl with a base to obtain pilocarpine. In an embodiment, themethod comprises treating pilocarpine HCl in a solvent with a base toobtain pilocarpine. In an embodiment, the method comprises treatingpilocarpine HCl in acetone with sodium hydrogen carbonate for about 18 hat room temperature to obtain pilocarpine. In an embodiment, the methodeffects yield of about 100%. In an embodiment, the method furthercomprises a step of effecting recrystallization of thepilocarpine-lipoate. In an embodiment, the step of effectingrecrystallization comprises effecting recrystallization ofpilocarpine-lipoate with ethyl acetate (5 volumes) at 50-55° C. toobtain crystalline pilocarpine-lipoate with yield of about 80%.

Another aspect of the present disclosure provides a method of synthesisof pilocarpine-(R)-lipoate, the method comprising: contactingpilocarpine with (R)-lipoic acid at a suitable temperature to obtainpilocarpine-(R)-lipoate. In an embodiment, the method comprisescontacting pilocarpine HCl with a base to obtain pilocarpine. In anembodiment, the method comprises treating pilocarpine HCl in a solventwith a base to obtain pilocarpine. In an embodiment, the methodcomprises treating pilocarpine HCl in acetone with sodium hydrogencarbonate for about 18 h at room temperature to obtain pilocarpine. Inan embodiment, the method effects yield of about 100%. However, a personskilled in the pertinent art would appreciate that any other method ofsynthesis of pilocarpine-(R)-lipoate, as known to or appreciated by aperson skilled in the art, can be suitably employed to sub-serve itsintended purpose without departing from the scope and spirit of thepresent disclosure.

In an embodiment, the method further comprises a step of effectingrecrystallization of the pilocarpine-(R)-lipoate. In an embodiment, thestep of effecting recrystallization comprises effectingrecrystallization of pilocarpine-(R)-lipoate with ethyl acetate (5volumes) at 50-55° C. to obtain crystalline pilocarpine-(R)-lipoate withyield of about 80%. However, it should be appreciated thatrecrystallization of the pilocarpine-(R)-lipoate can be effectedemploying any other method as known to or appreciated by a personskilled in the pertinent art without departing from the scope and spiritof the present invention.

Although several embodiments of the present disclosure describes themethod of preparation and recrystallization of pilocarpine-(R)-lipoate,it should be appreciated by a person skilled in the art, thesubstantially same or similar method can be used for synthesis ofpilocarpine-(R,S)-lipoate and/or pilocarpine-(S)-lipoate and the samehas not been described in detail for the sake of brevity.

Still further aspect of the present disclosure provides a method oftreating an eye disorder or complications thereof in a subject in needthereof, the method comprising administering to the subject atherapeutically effective amount of the compound of formula I or apharmaceutically acceptable hydrate, solvate, crystal, co-crystal,enantiomer, stereoisomer, polymorph or prodrug thereof. In anembodiment, the eye disorder that can be treated by the method disclosedherein can include macular degeneration, cataract, glaucoma, diabeticretinopathy, dry eye, ocular neuritis, retinitis pigmentosa andpresbyopia. In an embodiment, the compound of formula I can beadministered to said subject in combination with a pharmaceuticallyacceptable excipient. In an embodiment, the therapeutically effectiveamount of the compound of formula I that can be administered to saidsubject can range from 0.001 mg to 1000 mg. In an embodiment, thecompound of formula I can be administered topically to at least one eyeof a subject in need of treatment for eye disorder or complicationsassociated therewith.

In an embodiment, the compound of formula I that can be used in thetreatment method of the present disclosure can be selected from one ormore of:

The compounds of the present disclosure may be in the form of hydratesor solvates of acid moiety—lipoic acid and the base componentrepresented as X+ in which the acid component is in partially ionic formand the base component represented as X+ is protonated in thepharmaceutically acceptable salt. In some instances, however, forexample depending on the pH of the environment, the compounds may be inthe form of a mixture of X+ and lipoic acid.

Without wishing to bound by the theory, it is believed that pilocarpineaids in lowering intraocular pressure, induces miosis and assists inaccommodation in the eye, while lipoic acid acts as an anti-oxidant,regenerates glutathione and improves lens activity in the human eye.

Synthesis of Compounds of Formula I

Pilocarpine salt in a solvent can be treated with a base for a timeperiod to get free base of pilocapine, which upon contact with lipoicacid results in formation of compounds of Formula I. Alternatively,pilocarpine can be contacted with lipoic acid to directly obtaincompounds of Formula I. A person skilled in the pertinent art wouldappreciate that choice of solvent, base and process parameters liketemperature, time and the likes can be suitably amended/selected inorder to sub-serve its intended purpose and the scope of the presentdisclosure is not restricted to utilization of any specific solvent/baseand/or the process parameters.

In an embodiment, firstly, pilocarpine HCl in acetone is treated withsodium hydrogen carbonate for 18 h at room temperature to get free baseof Pilocarpine, which upon reaction with (R)-Lipoic acid at roomtemperature for 1 h gives Pilocarpine-(R)-Lipoate in about 100% yield.

In an embodiment, the pilocarpine-lipoate is recrystallized usingsuitable solvent or a combination of solvents to afford crystallinePilocarpine-Lipoate. Such solvent or combination of solvents are wellknown to a person skilled in the pertinent art and same has not beendescribed in detail for the sake of clarity. The technique ofrecrystallization is elaborately dealt with in “Remington—The Scienceand Practice of Pharmacy”, 20th. Ed., Lippincott Williams & Wilkins,Baltimore, Md., 2000”, contents of which are incorporated herein in itsentirety by way of reference. In an embodiment, Pilocarpine-(R)-Lipoateis recrystallized from ethyl acetate (5 volumes) at 50-55° C. to affordyellow crystalline Pilocarpine-(R)-Lipoate in about 80% yield.

The present disclosure also discloses pharmaceutical compositionscomprising a pharmaceutically acceptable excipient and one or acombination of compounds of Formula I that may be formulated forsystemic or topical or oral administration. The pharmaceuticalcomposition may be also formulated for oral administration, oralsolution, injection, subdermal administration, or transdermaladministration.

In many embodiments, the pharmaceutical compositions described hereinincorporate the disclosed compounds (Formula I) to be delivered in anamount sufficient to deliver to a patient, a therapeutically effectiveamount of a compound of Formula I, as part of a prophylactic ortherapeutic treatment. The desired concentration of compound(s) ofFormula I or its pharmaceutical acceptable hydrates or solvates willdepend on absorption, inactivation, and excretion rates of the drug aswell as the delivery rate of the hydrates or solvates and compositionsfrom the subject compositions. It is to be noted that dosage values mayalso vary with the severity of the condition to be alleviated. It is tobe further understood that for any particular subject, specific dosageregimens may need to be adjusted over time according to the individualneed and the professional judgment of the person administering orsupervising the administration of the compositions. Typically, dosingwill be determined using techniques known to one skilled in the art.

Additionally, the optimal concentration and/or quantities or amounts ofany particular compound of Formula I may be adjusted to accommodatevariations in the treatment parameters. Such treatment parameters mayinclude the clinical use to which the preparation is put, e.g., the sitetreated, the type of patient, e.g., human or non-human, adult or child,and the nature of the disease or condition, but not limited thereto.

The concentration and/or amount of any compound of Formula I may bereadily identified by routine screening in animals, e.g., rats, byscreening a range of concentration and/or amounts of the material inquestion using appropriate assays. Known methods are also available toassay local tissue concentrations, diffusion rates of the hydrates orsolvates or compositions, and local blood flow before and afteradministration of therapeutic formulations disclosed herein. One suchmethod is microdialysis, as reviewed by T. E. Robinson et al., 1991,microdialysis in the neurosciences, Techniques, volume 7, Chapter 1. Themethods reviewed by Robinson may be applied, in brief, as follows. Amicrodialysis loop is placed in situ in a test animal. Dialysis fluid ispumped through the loop. When compounds with Formula I such as thosedisclosed herein are injected adjacent to the loop, released drugs arecollected in the dialysate in proportion to their local tissueconcentrations. The progress of diffusion of the hydrates or solvates orcompositions may be determined thereby with suitable calibrationprocedures using known concentrations of hydrates or solvates orcompositions.

In certain embodiments, the dosage of the compounds of Formula Iprovided herein may be determined by reference to the plasmaconcentrations of the composition or other encapsulated materials. Forexample, the maximum plasma concentration (Cmax) and the area under theplasma concentration-time curve from time 0 to infinity may be used.

Generally, in carrying out the methods detailed in the presentdisclosure, an effective dosage for the compound of Formula I is in therange of about 0.01 mg/kg/day to about 100 mg/kg/day in single ordivided doses, for instance 0.01 mg/kg/day to about 50 mg/kg/day insingle or divided doses. The compounds of Formulas I may be administeredat a dose of, for example, less than 0.2 mg/kg/day, 0.5 mg/kg/day, 1.0mg/kg/day, 5 mg/kg/day, 10 mg/kg/day, 20 mg/kg/day, 30 mg/kg/day, or 40mg/kg/day. Compound of Formula I may also be administered to a humanpatient at a dose of, for example, between 0.001 mg and 1000 mg, between5 mg and 80 mg, or less than 1.0, 9.0, 12.0, 20.0, 50.0, 75.0, 100, 300,400, 500, 800, 1000, 2000, 5000 mg per day. In certain embodiments, thecompositions herein are administered at an amount that is less than 95%,90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, or 10% of the compound ofFormula I required for the same therapeutic benefit.

A therapeutically effective amount of the compound of Formula I asdescribed herein refers to an amount of the compound of formula I whichis sufficient to elicit the desired biological response. An effectiveamount may be sufficient to prohibit, treat, alleviate, ameliorate,halt, restrain, slow or reverse the progression, or reduce the severityof a complication resulting from intraocular pressure, optic nervecomplications, glaucoma, ocular lens complications, cataracts, lensthickening and refractive index problems of the eye. As such, thesemethods include both medical therapeutic (acute) and/or prophylactic(prevention) administration as appropriate. The amount and timing ofcompositions administered will, of course, be dependent on the subjectbeing treated, on the severity of the affliction, on the manner ofadministration and on the judgment of the prescribing physician. Thus,because of patient-to-patient variability, the dosages given above are aguideline and the physician may titrate doses of the drug to achieve thetreatment that the physician considers appropriate for the patient. Inconsidering the degree of treatment desired, the physician must balancea variety of factors such as age of the patient, presence of preexistingdisease, as well as presence of other diseases. In an exemplaryembodiment, the therapeutically effective amount of the compound ofFormula I can range from 0.001 mg to 1000 mg.

The compositions disclosed herein may be administered to a subject inneed of treatment by a variety of conventional routes of administration,including orally, topically, parenterally, e.g., intravenously,subcutaneously or intramedullary, but not limited thereto. Further, thecompositions may be administered intranasally, as a rectal suppository,or using a “flash” formulation, i.e., allowing the medication todissolve in the mouth without the need to use water. Furthermore, thecompositions may be administered to a subject in need of treatment bycontrolled release dosage forms, site specific drug delivery,transdermal drug delivery, patch (active/passive) mediated drugdelivery, by stereotactic injection, or in nanoparticles.

The compositions may be administered alone or in combination withpharmaceutically acceptable carriers, vehicles or diluents(collectively, referred to herein as excipients), in either single ormultiple doses. Suitable pharmaceutical carriers, vehicles and diluentsinclude inert solid diluents or fillers, sterile aqueous solutions andvarious organic solvents. The pharmaceutical compositions formed bycombining the compounds and the pharmaceutically acceptable carriers,vehicles or diluents are then readily administered in a variety ofdosage forms such as tablets, powders, lozenges, syrups, injectablesolutions and the likes. These pharmaceutical compositions may, ifdesired, contain additional ingredients such as flavorings, binders,excipients and the likes. Thus, for purposes of oral administration,tablets containing various excipients such as L-arginine, sodiumcitrate, calcium carbonate and calcium phosphate may be employed alongwith various disintegrating agents such as starch, alginic acid andcertain complex silicates, together with binding agents such aspolyvinylpyrrolidone, sucrose, gelatin and acacia. Additionally,lubricating agents such as magnesium stearate, sodium lauryl sulfate andtalc are often useful for tabletting purposes. Solid compositions of asimilar type may also be employed as fillers in soft and hard filledgelatin capsules. Appropriate materials for this include lactose or milksugar and high molecular weight polyethylene glycols, but not limitedthereto. When aqueous suspensions or elixirs are desired for oraladministration, the essential active ingredient may be combined withvarious sweetening or flavoring agents, coloring matter or dyes and, ifdesired, emulsifying or suspending agents, together with diluents suchas water, ethanol, propylene glycol, glycerin and combinations thereof.The compounds of Formula I may also be formulated as enterically coatedformulations including various excipients, as is well known in thepharmaceutical art.

For parenteral administration, solutions (compositions) may be preparedusing (for example) sesame or peanut oil, aqueous propylene glycol, orsterile aqueous solutions. Such solutions may be suitably buffered ifnecessary, and the liquid diluent is first rendered isotonic withsufficient saline or glucose. These particular aqueous solutions areespecially suitable for intravenous, intramuscular, subcutaneous andintraperitoneal administration. In this connection, the sterile aqueousmedia employed are all readily available by standard techniques known tothose skilled in the art.

The formulations, for instance tablets, may contain e.g. 10 to 100, 50to 250, 150 to 500 mg, or 350 to 800 mg e.g. 10, 50, 100, 300, 500, 700,800 mg of the compounds of Formula I disclosed herein, for instance,compounds of Formula I or pharmaceutical acceptable hydrates or solvatesof a compounds of Formula I.

Generally, a composition as described herein may be administered orally,or parenterally (e.g., intravenous, intramuscular, subcutaneous orintramedullary). Topical administration may also be indicated, forexample, where the patient is suffering from gastrointestinal disorderthat prevent oral administration, or whenever the medication is bestapplied to the surface of a tissue or organ as determined by theattending physician. Localized administration may also be indicated, forexample, when a high dose is desired at the target tissue or organ. Forbuccal administration the active composition may take the form oftablets or lozenges formulated in a conventional manner.

The dosage administered will be dependent upon the identity of thedisease; the type of host involved, including its age, health andweight; the kind of concurrent treatment, if any; the frequency oftreatment and therapeutic ratio, but not limited thereto.Illustratively, dosage levels of the administered active ingredientsare: ocular, 0.0001 to about 100 mg/kg; intravenous, 0.1 to about 200mg/kg; intramuscular, 1 to about 500 mg/kg; orally, 5 to about 1000mg/kg; intranasal instillation, 5 to about 1000 mg/kg; and aerosol, 5 toabout 1000 mg/kg of host body weight.

Expressed in terms of concentration, an active ingredient can be presentin the compositions of the present invention for localized use about thecutis, intranasally, pharyngolaryngeally, bronchially, intravaginally,rectally, or ocularly in a concentration of from about 0.01 to about 50%w/w of the composition; preferably about 1 to about 20% w/w of thecomposition; and for parenteral use in a concentration of from about0.05 to about 50% w/v of the composition and preferably from about 5 toabout 20% w/v.

The compositions of the present invention are preferably presented foradministration to humans and animals in unit dosage forms, such astablets, capsules, pills, powders, granules, suppositories, sterileparenteral solutions or suspensions, sterile non-parenteral solutions,suspensions, and oral solutions or suspensions and the like, containingsuitable quantities of an active ingredient. For oral administrationeither solid or fluid unit dosage forms can be prepared.

As discussed above, the tablet core may contain one or more hydrophilicpolymers. Suitable hydrophilic polymers include, but are not limited to,water swellable cellulose derivatives, polyalkylene glycols,thermoplastic polyalkylene oxides, acrylic polymers, hydrocolloids,clays, gelling starches, swelling cross-linked polymers, and mixturesthereof. Examples of suitable water swellable cellulose derivativesinclude, but are not limited to, sodium carboxymethylcellulose,cross-linked hydroxypropylcellulose, hydroxypropyl cellulose (HPC),hydroxypropylmethylcellulose (HPMC), hydroxyisopropylcellulose,hydroxybutylcellulose, hydroxyphenylcellulose, hydroxyethylcellulose(HEC), hydroxypentylcellulose, hydroxypropylethylcellulose,hydroxypropylbutylcellulose, and hydroxypropylethylcellulose, andmixtures thereof. Examples of suitable polyalkylene glycols include, butare not limited to, polyethylene glycol. Examples of suitablethermoplastic polyalkylene oxides include, but are not limited to,poly(ethylene oxide). Examples of suitable acrylic polymers include, butare not limited to, potassium methacrylatedivinylbenzene copolymer,polymethylmethacrylate, high-molecular weight crosslinked acrylic acidhomopolymers and copolymers such as those commercially available fromNoveon Chemicals under the tradename CARBOPOL™. Examples of suitablehydrocolloids include, but are not limited to, alginates, agar, guargum, locust bean gum, kappa carrageenan, iota carrageenan, tara, gumarabic, tragacanth, pectin, xanthan gum, gellan gum, maltodextrin,galactomannan, pusstulan, laminarin, scleroglucan, gum arabic, inulin,pectin, gelatin, whelan, rhamsan, zooglan, methylan, chitin,cyclodextrin, chitosan, and mixtures thereof. Examples of suitable claysinclude, but are not limited to, smectites such as bentonite, kaolin,and laponite; magnesium trisilicate; magnesium aluminum silicate; andmixtures thereof. Examples of suitable gelling starches include, but arenot limited to, acid hydrolyzed starches, swelling starches such assodium starch glycolate and derivatives thereof, and mixtures thereof.Examples of suitable swelling cross-linked polymers include, but are notlimited to, cross-linked polyvinyl pyrrolidone, cross-linked agar, andcross-linked carboxymethylcellulose sodium, and mixtures thereof.

The carrier may contain one or more suitable excipients for theformulation of tablets. Examples of suitable excipients include, but arenot limited to, fillers, adsorbents, binders, disintegrants, lubricants,glidants, release-modifying excipients, superdisintegrants, antioxidantsor mixtures thereof.

Suitable binders include, but are not limited to, dry binders such aspolyvinyl pyrrolidone and hydroxypropylmethylcellulose; wet binders suchas water-soluble polymers, including hydrocolloids such as acacia,alginates, agar, guar gum, locust bean, carrageenan,carboxymethylcellulose, tara, gum arabic, tragacanth, pectin, xanthan,gellan, gelatin, maltodextrin, galactomannan, pusstulan, laminarin,scleroglucan, inulin, whelan, rhamsan, zooglan, methylan, chitin,cyclodextrin, chitosan, polyvinyl pyrrolidone, cellulosics, sucrose, andstarches; and mixtures thereof. Suitable disintegrants include, but arenot limited to, sodium starch glycolate, cross-linkedpolyvinylpyrrolidone, cross-linked carboxymethylcellulose, starches,microcrystalline cellulose, and mixtures thereof. Suitable lubricantsinclude, but are not limited to, long chain fatty acids and theirhydrates or solvates, such as magnesium stearate and stearic acid, talc,glycerides waxes, and mixtures thereof. Suitable glidants include, butare not limited to, colloidal silicon dioxide. Suitablerelease-modifying excipients include, but are not limited to, insolubleedible materials, pH-dependent polymers, and mixtures thereof.

Suitable insoluble edible materials for use as release-modifyingexcipients include, but are not limited to, water-insoluble polymers andlow-melting hydrophobic materials, copolymers thereof, and mixturesthereof. Examples of suitable water-insoluble polymers include, but arenot limited to, ethylcellulose, polyvinyl alcohols, polyvinyl acetate,polycaprolactones, cellulose acetate and its derivatives, acrylates,methacrylates, acrylic acid copolymers, copolymers thereof and mixturesthereof. Suitable low-melting hydrophobic materials include, but are notlimited to, fats, fatty acid esters, phospholipids, waxes, and mixturesthereof. Examples of suitable fats include, but are not limited to,hydrogenated vegetable oils such as for example cocoa butter,hydrogenated palm kernel oil, hydrogenated cottonseed oil, hydrogenatedsunflower oil, and hydrogenated soybean oil, free fatty acids and theirhydrates or solvates, and mixtures thereof. Examples of suitable fattyacid esters include, but are not limited to, sucrose fatty acid esters,mono-, di-, and triglycerides, glyceryl behenate, glycerylpalmitostearate, glyceryl monostearate, glyceryl tristearate, glyceryltrilaurylate, glyceryl myristate, GlycoWax-932, lauroyl macrogol-32glycerides, stearoyl macrogol-32 glycerides, and mixtures thereof.Examples of suitable phospholipids include phosphotidyl choline,phosphotidyl serene, phosphotidyl enositol, phosphotidic acid, andmixtures thereof. Examples of suitable waxes include, but are notlimited to, carnauba wax, spermaceti wax, beeswax, candelilla wax,shellac wax, microcrystalline wax, and paraffin wax; fat-containingmixtures such as chocolate, and mixtures thereof. Examples of superdisintegrants include, but are not limited to, croscarmellose sodium,sodium starch glycolate and cross-linked povidone (crospovidone). In oneembodiment the tablet core contains up to about 5 percent by weight ofsuch super disintegrant.

Examples of antioxidants include, but are not limited to, tocopherols,ascorbic acid, sodium pyrosulfite, butylhydroxytoluene, butylatedhydroxyanisole, edetic acid, and edetate hydrates or solvates, andmixtures thereof. Examples of preservatives include, but are not limitedto, citric acid, tartaric acid, lactic acid, malic acid, acetic acid,benzoic acid, and sorbic acid, and mixtures thereof.

In one embodiment, the immediate release coating has an averagethickness of at least 50 microns, such as from about 50 microns to about2500 microns; e.g., from about 250 microns to about 1000 microns. Inembodiment, the immediate release coating is typically compressed at adensity of more than about 0.9 g/cc, as measured by the weight andvolume of that specific layer.

In one embodiment, the immediate release coating contains a firstportion and a second portion, wherein at least one of the portionscontains the second pharmaceutically active agent. In one embodiment,the portions contact each other at a center axis of the tablet. In oneembodiment, the first portion includes the first pharmaceutically activeagent and the second portion includes the second pharmaceutically activeagent.

In one embodiment, the first portion contains the first pharmaceuticallyactive agent and the second portion contains the second pharmaceuticallyactive agent. In one embodiment, one of the portions contains a thirdpharmaceutically active agent. In one embodiment one of the portionscontains a second immediate release portion of the same pharmaceuticallyactive agent as that contained in the tablet core.

In one embodiment, the outer coating portion is prepared as a dry blendof materials prior to addition to the coated tablet core. In anotherembodiment the outer coating portion is included of a dried granulationincluding the pharmaceutically active agent.

Formulations with different drug release mechanisms described abovecould be combined in a final dosage form containing single or multipleunits. Examples of multiple units include multilayer tablets, capsulescontaining tablets, beads, or granules in a solid or liquid form.Typical, immediate release formulations include compressed tablets,gels, films, coatings, liquids and particles that can be encapsulated,for example, in a gelatin capsule. Many methods for preparing coatings,covering or incorporating drugs, are known in the art.

The immediate release dosage, unit of the dosage form, i.e., a tablet, aplurality of drug-containing beads, granules or particles, or an outerlayer of a coated core dosage form, contains a therapeutically effectivequantity of the active agent with conventional pharmaceuticalexcipients. The immediate release dosage unit may or may not be coated,and may or may not be admixed with the delayed release dosage unit orunits (as in an encapsulated mixture of immediate releasedrug-containing granules, particles or beads and delayed releasedrug-containing granules or beads).

Extended release formulations are generally prepared as diffusion orosmotic systems, for example, as described in “Remington—The Science andPractice of Pharmacy”, 20th. Ed., Lippincott Williams & Wilkins,Baltimore, Md., 2000. A diffusion system typically consists of one oftwo types of devices, reservoir and matrix, which are well known anddescribed in the art. The matrix devices are generally prepared bycompressing the drug with a slowly dissolving polymer carrier into atablet form.

An immediate release portion can be added to the extended release systemby means of either applying an immediate release layer on top of theextended release core; using coating or compression processes or in amultiple unit system such as a capsule containing extended and immediaterelease beads.

Delayed release dosage formulations are created by coating a soliddosage form with a film of a polymer, which is insoluble in the acidenvironment of the stomach, but soluble in the neutral or slightly basicenvironment of small intestine. The delayed release dosage units can beprepared, for example, by coating a drug or a drug-containingcomposition with a selected coating material. The drug-containingcomposition may be a tablet for incorporation into a capsule, a tabletfor use as an inner core in a “coated core” dosage form, or a pluralityof drug-containing beads, particles or granules, for incorporation intoeither a tablet or capsule.

A pulsed release dosage form is one that mimics a multiple dosingprofile without repeated dosing and typically allows at least a twofoldreduction in dosing frequency as compared to the drug presented as aconventional dosage form (e.g., as a solution or prompt drug-releasing,conventional solid dosage form). A pulsed release profile ischaracterized by a time period of no release (lag time) or reducedrelease followed by rapid drug release.

Each dosage form contains a therapeutically effective amount of activeagent (compound of formula I). In one embodiment of dosage forms thatmimic a twice daily dosing profile, approximately 30 wt. % to 70 wt. %,preferably 40 wt. % to 60 wt. %, of the total amount of active agent inthe dosage form is released in the initial pulse, and, correspondinglyapproximately 70 wt. % to 30 wt. %, preferably 60 wt. % to 40 wt. %, ofthe total amount of active agent in the dosage form is released in thesecond pulse. For dosage forms mimicking the twice daily dosing profile,the second pulse is preferably released approximately 3 hours to lessthan 14 hours, and more preferably approximately 5 hours to 12 hours,following administration.

Another dosage form contains a compressed tablet or a capsule having adrug-containing immediate release dosage unit, a delayed release dosageunit and an optional second delayed release dosage unit. In this dosageform, the immediate release dosage unit contains a plurality of beads,granules particles that release drug substantially immediately followingoral administration to provide an initial dose. The delayed releasedosage unit contains a plurality of coated beads or granules, whichrelease drug approximately 3 hours to 14 hours following oraladministration to provide a second dose.

For purposes of transdermal (e.g., topical) administration, dilutesterile, aqueous or partially aqueous solutions (usually in about 0.1%to 5% concentration), otherwise similar to the above parenteralsolutions, may be prepared.

Methods of preparing various pharmaceutical compositions with a certainamount of one or more compounds of Formula I and/or other active agentsare known, or will be apparent in light of this disclosure, to thoseskilled in this art. For examples of methods of preparing pharmaceuticalcompositions, see Remington's Pharmaceutical Sciences, Mack PublishingCompany, Easton, Pa., 19th Edition (1995).

In addition, in certain embodiments, subject compositions of the presentapplication maybe lyophilized or subjected to another appropriate dryingtechnique such as spray drying. The subject compositions may beadministered once, or may be divided into a number of smaller doses tobe administered at varying intervals of time, depending in part on therelease rate of the compositions and the desired dosage.

Formulations useful in the methods provided herein include thosesuitable for oral, nasal, topical (including ophthalmic, buccal andsublingual), rectal, vaginal, aerosol and/or parenteral administration.The formulations may conveniently be presented in unit dosage form andmay be prepared by any methods well known in the art of pharmacy. Theamount of the compound that may be combined with a carriermaterial/excipient to produce a single dose may vary depending upon thesubject being treated, and the particular mode of administration.

Methods of preparing these formulations or compositions include the stepof bringing into association compound with the carrier and, optionally,one or more accessory ingredients. In general, the formulations areprepared by uniformly and intimately bringing into association acompound with liquid carriers, or finely divided solid carriers, orboth, and then, if necessary, shaping the product.

The compounds of Formula I described herein may be administered ininhalant or aerosol formulations. The inhalant or aerosol formulationsmay comprise one or more agents, such as adjuvants, diagnostic agents,imaging agents, or therapeutic agents useful in inhalation therapy. Thefinal aerosol formulation may for example contain 0.005-90% w/w, forinstance 0.005-50%, 0.005-5% w/w, or 0.01-1.0% w/w, of medicamentrelative to the total weight of the formulation.

In solid dosage forms for oral administration (capsules, tablets, pills,dragees, powders, granules and the like), the subject composition ismixed with one or more pharmaceutically acceptable carriers and/or anyof the following: (1) fillers or extenders, such as starches, lactose,sucrose, glucose, mannitol, and/or silicic acid; (2) binders, such as,for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and/or acacia; (3) humectants, such as glycerol;(4) disintegrating agents, such as agar-agar, calcium carbonate, potatoor tapioca starch, alginic acid, certain silicates, and sodiumcarbonate; (5) solution retarding agents, such as paraffin; (6)absorption accelerators, such as quaternary ammonium compounds; (7)wetting agents, such as, for example, acetyl alcohol and glycerolmonostearate; (8) absorbents, such as kaolin and bentonite clay; (9)lubricants, such a talc, calcium stearate, magnesium stearate, solidpolyethylene glycols, sodium lauryl sulfate, and mixtures thereof; and(10) coloring agents. In the case of capsules, tablets and pills, thepharmaceutical compositions may also comprise buffering agents. Solidcompositions of a similar type may also be employed as fillers in softand hard-filled gelatin capsules using lactose or milk sugars, as wellas high molecular weight polyethylene glycols and the like.

Liquid dosage forms for oral administration include pharmaceuticallyacceptable emulsions, microemulsions, solutions, suspensions, syrups andelixirs. In addition to the subject compositions, the liquid dosageforms may contain inert diluents commonly used in the art, such as, forexample, water or other solvents, solubilizing agents and emulsifiers,such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethylacetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butyleneglycol, oils (in particular, cottonseed, corn, peanut, sunflower,soybean, olive, castor, and sesame oils), glycerol, tetrahydrofurylalcohol, polyethylene glycols and fatty acid esters of sorbitan, andmixtures thereof.

Suspensions, in addition to the active ingredient, may containsuspending agents such as, for example, ethoxylated isostearyl alcohols,polyoxyethylene sorbitol, and sorbitan esters, microcrystallinecellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth,or mixtures thereof.

Dosage forms for transdermal administration include powders, sprays,ointments, pastes, creams, lotions, gels, solutions, patches, andinhalants. A subject composition may be mixed under sterile conditionswith a pharmaceutically acceptable carrier, and with any preservatives,buffers, or propellants that may be required. For transdermaladministration, the complexes may include lipophilic and hydrophilicgroups to achieve the desired water solubility and transport properties.

The ointments, pastes, creams and gels may contain, in addition tosubject compositions, other carriers, such as animal and vegetable fats,oils, waxes, paraffins, starch, tragacanth, cellulose derivatives,polyethylene glycols, silicones, bentonites, silicic acid, talc and zincoxide, or mixtures thereof. Powders and sprays may contain, in additionto a subject composition, excipients such as lactose, talc, silicicacid, aluminum hydroxide, calcium silicates and polyamide powder, ormixtures of such substances. Sprays may additionally contain customarypropellants, such as chlorofluorohydrocarbons and volatile unsubstitutedhydrocarbons, such as butane and propane.

Methods of delivering a composition or compositions via a transdermalpatch are known in the art. Exemplary patches and methods of patchdelivery are described in U.S. Pat. Nos. 6,974,588, 6,564,093,6,312,716, 6,440,454, 6,267,983, 6,239,180, and 6,103,275.

In another embodiment, a transdermal patch may include: a substratesheet comprising a composite film formed of a resin compositioncomprising 100 parts by weight of a polyvinyl chloride-polyurethanecomposite and 2-10 parts by weight of astyrene-ethylene-butylene-styrene copolymer, a first adhesive layer onthe one side of the composite film, and a polyalkylene terephthalatefilm adhered to the one side of the composite film by means of the firstadhesive layer, a primer layer which comprises a saturated polyesterresin and is formed on the surface of the polyalkylene terephthalatefilm; and a second adhesive layer comprising a styrene-diene-styreneblock copolymer containing a pharmaceutical agent layered on the primerlayer. A method for the manufacture of the above-mentioned substratesheet comprises preparing the above resin composition molding the resincomposition into a composite film by a calendar process, and thenadhering a polyalkylene terephthalate film on one side of the compositefilm by means of an adhesive layer thereby forming the substrate sheet,and forming a primer layer comprising a saturated polyester resin on theouter surface of the polyalkylene terephthalate film.

Another type of patch comprises incorporating the drug directly in apharmaceutically acceptable adhesive and laminating the drug-containingadhesive onto a suitable backing member, e.g. a polyester backingmembrane. The drug should be present at a concentration which will notaffect the adhesive properties, and at the same time deliver therequired clinical dose.

Transdermal patches may be passive or active. Passive transdermal drugdelivery systems currently available, such as the nicotine, estrogen andnitroglycerine patches, deliver small-molecule drugs. Many of the otherdrugs are too large to be delivered through passive transdermal patchesand may be delivered using technology such as electrical assist(iontophoresis) for large-molecule drugs.

Iontophoresis is a technique employed for enhancing the flux of ionizedsubstances through membranes by application of electric current. Oneexample of an iontophoretic membrane is given in U.S. Pat. No. 5,080,646to Theeuwes. The principal mechanisms by which iontophoresis enhancesmolecular transport across the skin are (a) repelling a charged ion froman electrode of the same charge, (b) electroosmosis, the convectivemovement of solvent that occurs through a charged pore in response thepreferential passage of counter-ions when an electric field is appliedor (c) increase skin permeability due to application of electricalcurrent.

Ocular formulations include, but are not limited to, liquid formulations(e.g., solutions, suspensions) for topical administration as well asformulation for injection or ocular insert administration. Preferably,the ocular formulation is formulated for topical administration such asan eye drop, swab, ointment, gel, or mist (for example, an aerosol orspray). In one embodiment, the formulation is an eye drop. For ocularformulations, the pharmaceutically acceptable excipients are selected tobe compatible with, and suitable for, ocular use. Such excipients arewell known in the art. In one embodiment, excipients may be selected toimprove the solubility of the agent. Exemplary excipients include, butare not limited to, buffers, tonicity agents, viscosity agents,preservatives, emulsifiers, salts, lubricants, polymers, solvents, andother known excipients for ocular pharmaceutical formulations.Appropriate amounts can be determined by one of ordinary skill in theart, but non-limiting exemplary amounts (in % by weight) are alsoprovided below.

In one embodiment, the pharmaceutical composition includes one or morebuffers to adjust or maintain the pH of the formulation. In oneembodiment, the pH is near physiological pH (pH of tears is about 7).Thus, the pH of the formulation can be about 6 to about 8, about 6.5 toabout 7.5, about 6.8 to about 7.2, about 7.1 to about 7.5, or about 7.In another embodiment, the pH is about 5.5. Thus, the pH of theformulation can be about 4 to about 7, about 4.5 to about 6, about 4.5to about 5.5, about 5.5 to about 6.5, about 5 to about 6, about 5.25 toabout 5.75, or about 5.5. Exemplary buffers include, but are not limitedto, phosphate buffers (e.g., sodium phosphate monobasic monohydrate,sodium phosphate dibasic anhydrous), borate buffers, and HBSS (Hank'sBalanced Salt Solution). In one embodiment, the buffer is a phosphatebuffer. In another embodiment, the buffer is sodium phosphate monobasicmonohydrate and/or sodium phosphate dibasic anhydrous. The buffer amount(amount of either total buffer or a single buffer excipient) can be 0.1%to about 1.0%, about 0.2% to about 0.6%, about 0.05% to about 0.5%,about 0.25% to about 0.45%, or about 0.25%, about 0.43%, or about 0.7%.In one embodiment, the buffer is about 0.05% to about 0.5% (e.g., about0.27%) sodium phosphate monobasic monohydrate and about 0.2% to about0.6% (e.g., about 0.43%) sodium phosphate dibasic anhydrous.

In one embodiment, the pharmaceutical composition includes one or moretonicity agents. Although the formulation may be hypertonic orhypotonic, isotonic formulations are preferred (260-320 mOsm). Exemplarytonicity agents include, but are not limited to, sodium chloride. Thetonicity agent amount can be about 0.1% to about 5%, about 0.1% to about2%, about 0.1% to about 1%, about 0.25% to about 0.75%, about 0.2% toabout 0.6%, or about 0.5%. In one embodiment, the tonicity agent isabout 0.2% to about 0.6% (e.g., about 0.5%) sodium chloride.

In one embodiment the pharmaceutical composition includes one or moreviscosity agents to increase the viscosity of the formulation. Exemplaryviscosity agents include, but are not limited to, cellulosic agents(e.g., hydroxypropyl methylcellulose), polycarbophil, polyvinyl alcohol.In one embodiment, the viscosity agent is a cellulosic agent, e.g.,hydroxypropyl methylcellulose. The viscosity agent amount can be about0.1% to about 5%, about 0.1% to about 2%, about 0.1% to about 1%, about0.1% to about 0.4%, or about 0.2%. In one embodiment, the viscosityagent is about 0.1% to about 0.4% (e.g., about 0.2%) hydroxypropylmethylcellulose.

In one embodiment, the pharmaceutical composition includes one or morepreservatives to minimize microbial contamination or to enhance shelflife. Exemplary preservatives include, but are not limited to,benzalkonium chloride (BAK), cetrimonium, chlorobutanol, edetatedisodium (EDTA), polyquaternium-1 (Polyquad®), polyhexamethylenebiguanide (PHMB), stabilized oxychloro complex (PURITE®), sodiumperborate, and SofZia®. The preservative amount may be, e.g., less thanabout 0.02%, about 0.004% or less, or about 0.005% to about 0.01%.

In one embodiment, the pharmaceutical composition includes one or morestabilizers. Exemplary stabilizers include, but are not limited to aminoacids such as alanine. The stabilizer amount can be about 0.1% to about5%, about 0.1% to about 2%, about 0.1% to about 1%, about 0.25% to about0.75%, about 0.2% to about 0.6%, or about 0.5%. In one embodiment, thestabilizer is about 0.2% to about 0.6% (e.g., about 0.5%) alanine.

In one embodiment, the pharmaceutical composition includes one or moreemulsifiers. Exemplary emulsifiers include, but are not limited to,Polysorbate 80.

The compounds described herein can be used in combination with oneanother, with other active agents known to be useful in ocular disease,or with adjunctive agents that may not be effective alone, but maycontribute to the efficacy of the active agent. For example, adjunctiveagents might include one or more amino acids or choline (separate fromthe lipoic acid compound) to enhance the efficacy of the active agent.The combinations can be advantageous, e.g., in reducing metabolicdegradation.

The term “co-administer” means to administer more than one active agent,such that the duration of physiological effect of one active agentoverlaps with the physiological effect of a second active agent. In someembodiments, co-administration includes administering one active agentwithin 0.5, 1, 2, 4, 6, 8, 10, 12, 16, 20, or 24 hours of a secondactive agent. Co-administration includes administering two active agentssimultaneously, approximately simultaneously (e.g., within about 1, 5,10, 15, 20, or 30 minutes of each other), or sequentially in any order.In some embodiments, co-administration can be accomplished byco-formulation, i.e., preparing a single pharmaceutical compositionincluding both active agents. In other embodiments, the active agentscan be formulated separately. In another embodiment, the active and/oradjunctive agents may be linked or conjugated to one another. In oneembodiment, one or more pharmaceutical excipients are selected from thegroup consisting of buffers, tonicity agents, and viscosity agents.

The pharmaceutical formulation may be packaged for administration by anymeans known in the art including, but not limited to, individual doseunits or multi-dose units, e.g., dropper bottles. Multi-dose units mayinclude, for example, about 1 mL to about 100 mL, about 1 mL to about 50mL, about 1 mL to about 10 mL, about 2 mL to about 7 mL, or about 5 mL.An individual dose may be, e.g., 1-10 drops, 1-5 drops, or 2-3 drops,wherein each drop is about 5 to about 50 μl, about 10 to about 30 μl, orabout 20 μl. Depending on the active agent concentration and thecondition of the patient, doses may be administered.

EQUIVALENTS

The present disclosure provides among other things compositions andmethods for treating neurological diseases and their complications.While specific embodiments of the subject disclosure have beendiscussed, the above specification is illustrative and not restrictive.Many variations of the systems and methods herein will become apparentto those skilled in the art upon review of this specification. The fullscope of the claimed systems and methods should be determined byreference to the claims, along with their full scope of equivalents, andthe specification, along with such variations.

INCORPORATION BY REFERENCE

All publications and patents mentioned herein, including those itemslisted above, are hereby incorporated by reference in their entirety asif each individual publication or patent was specifically andindividually indicated to be incorporated by reference. In case ofconflict, the present application, including any definitions herein,will control.

EXAMPLES Synthesis of Compound of Formula I

Stage 1: Pilocarpine HCl in acetone was treated with sodium hydrogencarbonate for 18 h at room temperature to get free base of Pilocarpinewhich upon reaction with (R)-Lipoic acid at room temperature for 1 hgave Pilocarpine-(R)-Lipoate [5-(((3R,4S)-4-ethyl-5-oxotetrahydrofuran-3-yl)methyl)-1-methyl-1H-imidazol-1-ium(R)-5-(1,2-dithiolan-3-yl)pentanoate] in ˜100% yield.

Stage 2: Stage 1 product was recrystallized from ethyl acetate (5volumes) at 50-55° C. to afford yellow crystallinePilocarpine-(R)-Lipoate n˜80% yield.

Characterization of Pilocarpine-(R)-Lipoate By NMR

1H-NMR of Pilocarpine-(R)-Lipoate in DMSO-d6 solvent was obtained, andthe chemical shift value for corresponding protons are provided in theTable 1 hereinbelow.

TABLE 1 Chemical shift value of 1H-NMR of Pilocarpine-(R)-LipoateChemical shift Position of the protons (in δ ppm with multiplicity) 27Protons corresponding to δ 0.99-1.02 (3H, t) aliphatic carbons δ1.34-1.40 (2H, m) δ 1.47-1.57 (4H, m) δ 1.62-1.71 (2H, m) δ 1.84-1.90(1H, m) δ 2.18-2.22 (2H, t) δ 2.31-2.43 (2H, m) δ 2.63-2.85 (3H, m) δ3.08-3.21 (2H, m) δ 3.53 (3H, s) δ 3.59-3.63 (1H, m) δ 3.94-3.97 (1H, m)δ 4.18-4.22 (1H, m) 2 Protons corresponding to aromatic δ 6.71 (1H, s)carbons of the imidazole ring δ 7.51 (1H, s) 1 Proton corresponding to δ12.02 (1H, bs) quaternary NH⁺

Ocular Pharmacokinetic Study

A pharmacokinetics study was conducted on male New Zealand white rabbitsto evaluate the ocular pharmacokinetics of CLX-156(Pilocarpine-(R)-Lipoate) formulation. Animals were topicallyadministered with 50 μL of CLX-156 in each eye, and the aqueous humourand blood samples were collected followed by sacrifice of the animalsfor collection of lens, cornea and iris region at a pre-determined time.

Composition Per microlitre Pilocarpine-(R)-Lipoate 29.4 mg* Glycerin 27mg L-Alanine 5 mg Water for Injection . . . qs 1 mL *Approximateequivalent to 14.7 mg of R-lipoate

The aqueous humour and tissue concentration of Pilocarpine and(R)-Lipoic acid were measured at 0.5 h, 1 h, 2 h, 4 h and 8 h in 3animals/time point/group (as provided in Table 2 and Table 3hereinbelow). Further, (R)-Lipoic acid concentration was measured in thelens region, and Pilocarpine concentration was measured in iris regionof each of the treated animals (as provided in Table 2 and Table 3). Allthe samples were analyzed using LCMS-MS by a fit for purpose method.

TABLE 2 Concentration of (R)-Lipoic acid in aqueous humour and lensregion, observed during the pharmacokinetics study. Concentration of(R)- Concentration of (R)- Parameters Lipoic acid in aqueous humourLipoic acid in lens region C_(max) 21.067 (μg/mL) 0.122 (μg/g) T_(max)0.50 (h) 0.50 (h) AUC_(last) 17.271 (μg*h/mL) 0.364 (μg*h/g)

TABLE 3 Concentration of Pilocarpine in aqueous humour and iris region,observed during the pharmacokinetics study. Concentration Concentrationof Pilocarpine of Pilocarpine Parameters in aqueous humour in irisregion C_(max) 6.48 (μg/mL) 1.962 (μg/g) T_(max) 0.50 (h) 0.50 (h)AUC_(last) 6.359 (μg*h/mL) 1.491 (μg*h/g)

From the aforesaid study and results obtained therefrom, followingobservations were made—(a) maximum concentration of (R)-Lipoic acid,present in the aqueous humour and lens region was 21.067 μg/mL and 0.122μg/g, respectively; (b) the (R)-Lipoic acid was detectable up to 2 to 4h in the aqueous humor, however, sustained level of (R)-Lipoic acid wasobserved from 2 to 8 h in the lens region, in animals treated withCLX-156 formulation; (c) maximum concentration of pilocarpine present inthe aqueous humour and iris region were found to be 6.48 μg/mL and 1.962μg/g, respectively; (d) pilocarpine was detectable up to 4 h and 2 h inaqueous humour and iris region in animals treated with CLX-156formulation.

The present disclosure provides compounds that provide bettertherapeutic benefit to patients and individuals suffering from eyedisorders. The compound(s) of Formula I of the present disclosure aid(s)in reduction of elevated intraocular pressure (TOP) in patients withopen-angle glaucoma or ocular hypertension, in management of acuteangle-closure glaucoma, in prevention of postoperative elevated IOPassociated with laser surgery, and induction of miosis, and improveslens elasticity and enhances accommodation of the eye in Presbyopics.The compound(s) of Formula I advantageously effects stabilization oflipoic acid and improves bioavailability thereof in ocular tissues.Accordingly, compositions of the present disclosure, including one ormore compounds of Formula I, exhibits enhanced therapeutic activity andefficacy including superior safety and tolerability.

While the foregoing describes various embodiments of the invention,other and further embodiments of the invention may be devised withoutdeparting from the basic scope thereof. The scope of the invention isdetermined by the claims that follow. The invention is not limited tothe described embodiments, versions or examples, which are included toenable a person having ordinary skill in the art to make and use theinvention when combined with information and knowledge available to theperson having ordinary skill in the art.

I claim:
 1. A compound of formula I:

or a pharmaceutically acceptable hydrate, solvate, crystal, co-crystal,enantiomer, stereoisomer, polymorph or prodrug thereof, wherein X⁺represents


2. The compound of claim 1, wherein the compound is selected from thegroup consisting of


3. The compound of claim 1, for use in treating an eye disorder orcomplications thereof, wherein said eye disorder is selected from thegroup consisting of macular degeneration, cataract, glaucoma, diabeticretinopathy, dry eye, ocular neuritis, retinitis pigmentosa andpresbyopia.
 4. A pharmaceutical composition comprising at least onecompound of claim 1 and a pharmaceutically acceptable excipient.
 5. Apharmaceutical composition comprising at least one compound of claim 2and a pharmaceutically acceptable excipient.
 6. The pharmaceuticalcomposition of claim 4, wherein said composition is formulated for oral,nasal, topical, rectal, vaginal, aerosol or parenteral administration.7. The pharmaceutical composition of claim 5, wherein said compositionis formulated for oral, nasal, topical, rectal, vaginal, aerosol orparenteral administration.
 8. The pharmaceutical composition of claim 4,wherein said composition is selected from the group consisting of atopical ophthalmic formulation and ophthalmic drop formulation.
 9. Thepharmaceutical composition of claim 5, wherein said composition isselected from the group consisting of a topical ophthalmic formulationand ophthalmic drop formulation.
 10. A method of synthesis of thecompound of claim 1, the method comprising treating pilocarpine withlipoic acid.
 11. A method of synthesis of the compound of claim 2, themethod comprising treating pilocarpine with lipoic acid.
 12. Amedicament for treatment of an eye disorder or complications associatedtherewith comprising a compound of claim
 1. 13. A medicament fortreatment of an eye disorder or complications associated therewith,comprising a compound of claim
 2. 14. A method of treating an eyedisorder or complications thereof in a subject, wherein the methodcomprises administering to said subject a therapeutically effectiveamount of a compound of formula I

or a pharmaceutically acceptable hydrate, solvate, crystal, co-crystal,enantiomer, stereoisomer, polymorph or prodrug thereof, wherein X⁺represents


15. The method of claim 14, wherein said compound is selected from thegroup consisting of


16. The method as claimed in claim 14, wherein said administeringcomprises oral, nasal, topical, rectal, vaginal, aerosol or parenteraladministration of said compound.
 17. The method as claimed in claim 14,wherein said compound is administered to said subject in combinationwith a pharmaceutically acceptable excipient.
 18. The method as claimedin claim 14, wherein said compound is administered topically in a formof an eye drop, a swab, an ointment, a gel or a mist.
 19. The method asclaimed in claim 14, wherein said compound is administered topically toat least one eye of said subject.
 20. The method as claimed in claim 14,wherein said therapeutically effective amount of said compound rangesfrom 0.001 mg to 1000 mg.
 21. The method as claimed in claim 14, whereinsaid subject is a human.
 22. The method as claimed in claim 14, whereinsaid eye disorder is selected from the group consisting of maculardegeneration, cataract, glaucoma, diabetic retinopathy, dry eye, ocularneuritis, retinitis pigmentosa and presbyopia.